Over the past year, we have initiated a new cancer genetics program within this Branch. The prototype cancer that will serve as a starting point for the delineation of a genetic approach to cancer prevention, surveillance, screening, counseling, and targeted therapy is colorectal cancer. Patients will enter the colorectal cancer genetics program because they present with a tumor that demonstrates microsatellite instability, or by presentation with a family history consistent with hereditary non- polyposis colorectal cancer. Once enrolled in the program, these patients will participate in a formalized genetic counseling protocol designed to inform, educate, and provide critical information about sequelae of counseling while, judiciously and formally establishing safeguards for the patient's ethical, legal, and social rights and expectations. Within the protocol, is a promise to offer testing for germline mutation of MSH2, MLH1, PMS1, and PMS2 at some point in the future. Depending on the therapy they have received for their malignancy or family histories and their medical coverage, patients will either be offered the opportunity to participate in colorectal cancer prevention and surveillance protocols or given recommendations for receiving such intervention from personal providers. A second aspect of this program is focused on the development of therapy specifically targeted at mismatch repair defective malignancies. Three components of this aspect of the program are: (1) a retrospective analysis of response to fluorouracil/leucovorin-based therapy and survival of patients with mismatch repair defective (RER+) colorectal cancers compared to a matched population with RER- malignancies. This will be coupled with a similar prospective analysis. (2) A study of the response of RER+ versus RER- colorectal and ovarian cancer cell lines to a myriad of chemotherapeutic agents utilizing the database of the NCI drug screening program. (3) A targeted cytotoxicity assay using cell lines that are genotypically essentially identical except for their mismatch repair competency. The underlying hypotheses for this component of the work is that since mismatch repair defective cells do not recognize or repair mismatches as effectively as normal cells, it should be possible to incorporate substituted and mismatch-engendering compounds into these cells.